The invention relates to a dry-coated tablet for controlled release of active substances. The dry-coated tablet is intended to allow active substances to be released in liquid media, for example body fluids, in a delayed manner and/or with the desired rate profile.
Tablets are often used particularly for the purpose of oral administration of pharmaceutical active substances. Depending on the therapeutic objective, a distinction may in this context be made between tablets with rapid release of active substance and those with controlled release of active substance. A controlled release of active substance is sought if, for example, the active substance has a short biological half-life. In this case, administration in the form of rapid-release tablets would lead to considerable fluctuations in the active substance plasma concentrations, unless small doses were taken at short intervals. Experience shows that patients seldom comply with prescribed intake frequencies of this kind, and this leads to failure of the treatment. The intake of tablets whose active substance release is controlled in such a way that it takes place with uniform delay over a period of several hours can keep the fluctuation of the active substance plasma concentrations to a minimum, while at the same time the low frequency of intake improves patient compliance. The therapeutically required delivery of active substance is guaranteed in this way, whilst the danger represented by particularly high plasma concentration peaks is avoided.
A delayed release of active substance can be achieved in different ways. It can be accomplished, on the one hand, by physical-chemical measures to which an active substance is subjected. Such measures include, for example, the use of active substance adsorbates, sparingly soluble active substance salts and complexes.
However, a greater control over the degree of delay is generally achieved by galenic techniques. Many of the known delayed-release tablets can be assigned to the matrix systems on the one hand or the membrane systems on the other hand. Matrix systems contain active substances in dissolved and suspended form, more rarely also in the form of a multi-particle pharmaceutical intermediate. Release takes place either by diffusion of active substances from the matrix or by continuous erosion of the matrix, starting at the edge zones. Membrane systems, by contrast, comprise a reservoir containing active substance, which reservoir is covered with a coating which is semi-permeable at least for the active substance. The release in this case takes place by means of diffusion of the active substance through the membrane.
The rate of release in these systems depends on various influencing factors. In the case of matrix tablets, these factors include, inter alia, the specific properties of the auxiliaries used, such as molar weight, solubility, swellability and glass transition temperature, but also the active substance concentration and the geometric shape of the matrix. In the case of release by diffusion from a matrix, the important factors include the size of the active surface, the matrix volume, the coefficient of diffusion, the concentration and solubility of the active substance in the matrix, the porosity and tortuosity of the matrix, and the diffusion resistance between matrix and a surrounding liquid medium. Coated tablets release active substances at a rate which primarily depends on the size of the active surface, the permeability of the active substance through the membrane, and the concentration gradient on both sides of the membrane.
With conventional matrix tablets and film-coated tablets, the rate of release can be controlled only to a limited extent. The realization of a uniformly delayed release runs into difficulties in both cases. In the case of erodible matrices, the rate of release changes to a greater or lesser extent, depending on the shape of the matrix, during the course of the release, on account of the change in the erodible surface. In the case of diffusion matrices, on the other hand, a diffusion layer which grows as the active substance depletion increases is built up during the course of release, with the consequence that the rate of release decreases as a function of t.sup.1/2 +L (Higuchi, J. Pharm. Sci. 50, p. 874, 1961).
An improved control over the release profile was achieved through the introduction of further control mechanisms. For example, EP-A 0 432 607 describes a multi-layer tablet whose matrix containing active substance represents one of the layers, which is partially covered by auxiliary layers. U.S. Pat. No. 3,924,622 describes the use of geometric elements, although the device which is claimed in the latter for controlled release of active substance is not a tablet. Nevertheless, the geometric control principle of compensatory surface enlargement is described here, by which control principle the factors slowing release--prolongation of the diffusion path, active substance depletion, etc.--are counteracted. The device is designed such that it has an active substance reservoir with a defined, constant opening through which the active substance passes outwards. The release takes place by means of erosion of the reservoir. The shape of the reservoir is chosen such that the erosion surface is continuously enlarged as the distance of the erosion front from the opening increases during the course of the release.
The devices described in EP-A 0 542 364 are based on a similar control mechanism. In these devices too, a surface, namely the diffusion front, increases in size during the course of the release. This has the same maintaining effect on the rate of release as does the geometric element in U.S. Pat. No. 3,924,622. Express mention is made of the possibility of embodiment as a tablet, the requirements in respect of the preferred design being somewhat complex.
EP-A 0 259 219 describes a coated tablet with a central opening thorough which the active substance is released outwards from the core tablet. The thickness of the core tablet increases from the central opening towards the periphery, as a result of which, analogously to the above-described systems, the distance, increasing during the course of release, between the erosion or diffusion front and the opening is compensated by a surface enlargement.
A compensation mechanism of another kind is described in unpublished German Patent Application P 43 41 442.7. This concerns a device with a matrix which contains active substance and which is initially partially covered by erodible auxiliary layers with thickness gradients, and these auxiliary layers erode during the course of the release and thereby bring about an enlargement of the matrix surface actively available for release.
A similarly effective control over the rate of release can be achieved using osmotic systems. These include a coated active substance and auxiliary substance reservoir in which an osmotic pressure builds up after admission of water. The membranes which surround the active substance reservoirs are semi-permeable; they permit the entry of water, but are impermeable to active substances, and yet have an almost microscopically small opening through which water which has diffused inwards can escape together with dissolved active substance. With such osmotic systems it was sometimes possible to achieve constant rates of release over a relatively long period (Theuwes, Pharm. Int. 5, 293, 1984).
All of these devices for controlled release of active substance have, compared to conventional delayed-release tablets of simple design, the advantage of being able to control the rate of release to a considerably greater extent. In the case of the precise osmotic systems, this is true in particular when a release of zero order is sought. The devices with geometric control elements are more variable in this respect and can also be used more suitably for achieving other release profiles.
However, compared to the conventional delayed-release tablets, many of the proposed embodiments have the disadvantage that they are very costly to produce. This is all the more so with the osmotic systems in which the conventional tabletting technology cannot as yet be used and the inclusion of an opening in the coating demands the very highest precision and reproducibility and can be accomplished only with the aid of expensive technologies and with limited manufacturing efficiency.